Hepatitis C virus (HCV) is the etiologic agent of non-A, non-B hepatitis. HCV is now the most common cause of chronic liver disease in the United States and has surpassed alcoholic liver disease as the most common indication for liver transplantation in North America. An estimated 1.8% of all Americans are infected with a higher percentage among African Americans (AA). A hallmark of the disease is its chronicity with up to 85% of those exposed having chronic infection. The UTHSC Memphis Hepatitis C Cooperative Research Center was established to support clinical and basic research to understand the basis for chronic disease in HCV infection and response to therapy in clinically infected patients. The population of the greater Memphis area is 55% AA within which there is a significant problem with chronic HCV infection. The well documented poor response rate of AA to combination therapy exacerbates the obvious health problem of chronic HCV in this region. The primary research goal of the Memphis Hepatitis C Cooperative Research Center and this project is to understand why AA are more susceptible to chronic infection and why then response rate to combination therapy is only 50% or less of that for non AA patients. The project builds upon the success and achievements of the Center to implement a truly multidisciplinary approach for hypothesis-driven research to understand why there are racial differences in susceptibility to chronic disease and response to therapy. In addition, the program will seek to identify novel small molecule inhibitors that inhibit interaction between viral ligands or their receptors for development of a new generation of therapeutic modalities. The proposed research program for the Center includes two projects, an administrative core, and a clinical core. Project 1 will determine how HLA class II- dependent immune regulation and T cell specificities affect differences in immune responses to HCV and response to therapy in AA compared to non AA patients. Project 2 will determine if there is a difference in interferon-induced signaling between patients that respond to therapy and those that do not. Each project will require the patient resources provided by the outstanding clinical core.